This application is the first step in an investigative program intended to test a novel hypothesis regarding the pathogenesis of juvenile idiopathic arthritis (JIA): the fundamental pathologic process in polyarticular JIA is not the inappropriate recognition of a self antigen by cells of the adaptive immune system, but, rather, the loss transcriptional regulation and cohesion, so that genes which are typically suppressed as an inflammatory response subsides remain in a partially-activated state. The investigators aim to test this hypothesis using functional genomics and computational biology approaches in a partnership between investigators at the University of Oklahoma College of Medicine and the Center for Genome Sciences & Systems Biology at Washington University in St. Louis. In order to achieve the long-term aims of this program, it is highly desirable that there be a focused period of interaction between the basic science investigators and the clinician-scientist (Dr. Jarvis) who is the primary applicant. The aim of this application is to provide an intense experience in which each of the groups learns the language of the other, so that the anticipated studies can be appropriately designed in such a way that they can be addressed by current (and evolving) computational approaches. It will be important for the computational group to understand the nuances of the JIA phenotype and treatment and the potential role of innate and adaptive immunity in this process. At the same time, this F33 application is designed to provide Dr. Jarvis with a deeper understanding of functional genomics and computational biology. The project will begin with parallel DNA methylation and whole-transciptome analyses of neutrophils from patients currently being seen in Oklahoma City and enrolled in R01-AR-060604, Microarray-Based Biomarkers In Juvenile Idiopathic Arthritis (James N. Jarvis, P.I.). Using these samples as preliminary data, the applicant will work with Dr. Ting Wang and computational colleagues (Drs. Nan Lin and Rob Mitra) to assess biological and technical variability and limits of existing computational approaches for handling 2 genome-wide data sets in the setting of a complex illness. Specific technical and computational approaches required to test the underlying hypothesis will then be developed by Drs. Jarvis, Wang, Lin, and Mitra. Dr. Jeff Millbrandt, the Chair of Genetics at Washington University, and Dr. John Atkinson, a rheumatology investigator with a longstanding interest in the genetics of rheumatic diseases, will serve as co-hosts. Each will assist the applicant in critiquing the work and directing him to other resources available on campus that will be useful in accelerating his research program. PUBLIC HEALTH RELEVANCE: Juvenile arthritis is one of the most common chronic disease conditions in children. This is a project that is intended to bring the latest advances in genome science into the study of juvenile arthritis and related disorders. In this project, the applicant,Dr. Jarvis, will work hand-in-hand with genome experts at Washington University in St. Louis to develop research approaches to study one of the severe forms of childhood arthritis.